The long-term goal is to develop a novel immune therapeutic approach to treating chronic HBV infection. There is currently no cure for the 350 million patients who are already chronically infected with hepatitis B virus (HBV). HBV replication can be effectively inhibited by anti-HBV drugs, but HBsAg is still expressed from HBV cccDNA or integrated genomes. The mechanisms of HBV-induced liver diseases, including chronic infection, immune responses, fibrosis/cirrhosis and liver cancer, are unclear due to a lack of relevant animal models. This project will take advantage of four key novel advancements in the PIs' groups: i) a novel humanized mouse model with human immune system & human liver (AFC8-hu HSC/Hep mice) that supports HBV infection, immune responses, hepatitis and fibrosis in the humanized liver; ii) human monoclonal antibodies (mAb) with high affinity to HBsAg that can neutralize HBV and clear extracellular HBs in vivo; iii) the newly developed AAV/HBV1.3 model in immune competent neonate and young adult mice; and iv) the LIGHT-based therapeutic vaccine approach that overcomes immune tolerance in the liver. We hypothesize that, by reducing HBV virions/HBsAg with antivirals and high affinity HBs mAb, the LIGHT-based HBV therapeutic vaccine will be effective to break HBV-induced immune tolerance, induce anti-HBV immunity and cure HBV infection. With complementary expertise, the two PIs will thus address the following specific questions related to HBV- induced immunopathology and immune therapeutics: (i) How does HBV infection modulate human T cell function in the liver and spleen/LN in vivo? (ii) What is the role of HBV persistence and PD1/TIM3 in impaired human immune responses in the liver? (iii) Will Ad-LIGHT-HBs vaccination (with HBs clearance mAb and antiviral) be able to cure an ongoing HBV infection? (iv) Is preS1 a better target than HBsAg to break tolerance to induce HBV neutralizing antibodies? Answers to these questions will have a significant impact on the field. The key findings will be confirmed in HBV-infected patients, and in future clinical trials.